The present invention relates to m-amino-phenylimino-imidazolidine derivatives with a new pattern of substituents at the phenyl ring and the use of m-amino-phenylimino-imidazolidine derivatives for the preparation of pharmaceutical compositions, particularly for treating urinary incontinence, and processes for preparing them.
The compounds described within the scope of the present invention belong to the category of the m-amino-phenylimino-imidazolidines. Similar compounds are known from the prior art.
Thus, for example, EP-A-0 236 636, inter alia, describes m-amino-phenylimino-imidazolidine derivatives with a primary amino function in the 3 position and their use as hemostatic agents. Clonidine derivatives of this kind are also discussed in EP-A-0 070 084, EP-A-0081923, EP-A-01 17102, EP-A-0 149 140, DE-A-2806811 or DE-A-2854659. Furthermore, U.S. Pat. No. 4,587,257 and EP-A-0081924 disclose m-amino-phenylimino-imidazolidine derivatives having a primary or acetylated amino function which can be used in ophthalmology. Biochem. Pharmacol. 32 (12) (1983), pp. 1933-1940, in another context discloses, inter alia, 2-(3-amino-2,6-dichlorophenylimino)imidazolidines. U.S. Pat. No. 4,287,201, for example, describes 2-(3-diethylamino-2-methylphenylimino)imidazolidines for increasing egg production in hens. Among others, WO 95/19968 discloses aminophenyliminoimidazole derivatives which are used as alpha 2 agonists in anesthesia, in the treatment of pain, high blood pressure, or hyperglycemia, or as soporifics.
WO 96/32939, which is hereby incorporated by reference in its entirety, discloses phenylimino-imidazoles, including those in which the phenyl ring has a primary or tertiary amine, an amide or imide in the meta position to the imino function. The compounds described therein count as alpha-1L-agonists and can advantageously be used in this capacity for treating urinary incontinence.
By incontinence is meant the involuntary release of urine, i.e., weakness of the bladder. The various forms of urinary incontinence include urge incontinence, reflex incontinence, overflow incontinence and stress or load incontinence. The most common forms of urinary incontinence include load incontinence or stress incontinence. These affect women in particular after more or less difficult childbirth. The reason for this is that pregnancy and childbirth can easily lead to weakening of the pelvic floor. Other causes of incontinence may be found, for example, in damage to the nerves of the pelvic floor, a congenitally short urinary tract or damage to the sphincter muscle.
The use of alpha-IL-agonists in the treatment of urinary incontinence is advantageous because they act selectively on the adrenoceptors of the bladder and thus exert a major influence on the tone of the ureter without significantly affecting the cardiovascular system.
In the prior art the possibility of using imidazole derivatives to treat incontinence has long been discussed. Surprisingly, there are opinions which indicate that many imidazole derivatives can counteract weakness of the bladder, whereas other authors have observed an apparently directly opposite effect, namely that substances of this kind can relieve obstruction of the bladder. Still other authors, talking about some of the same substances, report that they would have no effect at all on bladder function.
Thus, it is reported that alpha 2 agonists such as clonidine would have a positive effect on nocturnal incontinence (Urology, 43 (3) (1994), pp. 324-327). On the other hand, in respect of clonidine itself, there is the contrary observation that this substance might even promote incontinence (Clin. Biol. Res. 78 (1981), pp. 101-103) and a similar observation is expressed in Jpn. J. Pharmacol. 58 (4) (1992), pp. 339-346. The authors find that clonidine does not have a distinct influence on bladder function but that phenyl-ethanol-amines such as phenylephrine, midodrine or ST 1059, which are similar to adrenaline, and are all alpha 1 agonists, do have such an effect. EP-A-0 416 841 also deals with the influence of alpha agonists on bladder function. It describes how alpha 1 adrenoceptor-blocking substances could be used to treat obstruction of the bladder. The observations according to U.S. Pat. No. 4,226,773, also point in this direction. According to this specification, pyrazolyliminoimidazole derivatives can be used to promote the release of urine. Other alpha 1 adrenergic imidazoles such as thiophene-pyrroles, for example, may be used to treat urinary incontinence (EP-A-0 599 697).
These different observations from the prior art lead one to conclude that up till now it has been impossible to predict the influence of imidazole derivatives on bladder function.
Compounds which may be used to treat urinary incontinence not only have to be sufficiently effective but should also have as few side effects as possible. In other words, if possible they should act selectively on the bladder only. Undesirable side effects include, among other things, a negative effect on the cardiovascular system. For particularly effective treatment of urinary incontinence, the bioavailability of the substances and their metabolism are also of particular importance. The bioavailability should be as great as possible and the metabolism should be such that the substances are not broken down too rapidly on the one hand and no toxic compounds or other compounds having undesirable pharmacological properties in this context are formed on the other hand.
It is therefore an objective of the present invention to find new alpha-1L-agonists from the category of the phenyliminoimidazolidines which are identical or similar in their activity to the compounds known from the prior art, which act selectively on the bladder without substantially affecting the cardiovascular system and have enhanced qualities in terms of their bioavailability or metabolism.
Surprisingly, it has been found that the m-amino-phenylimino-imidazolidines according to the invention meet the objective of the present invention and are therefore particularly suitable for treating urinary incontinence. For the use of these compounds in connection with urinary incontinence it is essential on the one hand that the amino group is a tertiary amine and on the other hand that the other positions of the phenyl ring are substituted in a particular way.
According to the invention, the m-amino-phenylimino-2-imidazolidine derivatives of general formula I are used for the preparation of medicaments for the treatment of urinary incontinence: 
wherein:
R1 denotes F, Cl, Br, CH2F, CF2H, and/or CF3;
R2 denotes NR6R7, where
R6 denotes Me, Et, Pr or iPr,
R7 denotes Me, Et or Pr; and
R3, R4, and R5 independently of one another each denote H, Me, F, Cl, Br, CH2F, CF2H and/or CF3, and, in the event that R4 denotes Me, F, Cl, Br or CF3, then R1 additionally also denotes H or Me.
Me denotes methyl, CF3 denotes trifluoromethyl, CH2F denotes fluoromethyl, CF2H denotes difluoromethyl, Et denotes ethyl, Pr denotes propyl, iPr denotes isopropyl, H denotes hydrogen, F denotes fluorine, Cl denotes chlorine, Br denotes bromine, and N represents nitrogen.
Of these compounds with the hereinbefore-given structural formula, compounds of formula I are preferred wherein:
R1 denotes F, Cl, Br, or CF3;
R2 denotes NR6R7, where
R6 denotes Me or Et,
R7 denotes Me or Et; and
R3, R4, and R5 independently of one another each denote H, F, Cl, Br, and/or CF3.
Also preferred are those compounds of formula I wherein R1 may additionally also denote H or Me if R4 is F, Cl, Br or CF3.
Particularly preferred are compounds of formula I wherein:
R1 denotes Me;
R2 denotes NR6R7, where
R6 denotes Me or Et, preferably Me,
R7 denotes Me or Et, preferably Me;
R3 denotes H, F, Br or CF3;
R4 denotes Cl, Br or CF3; and
R5 denotes H, Br or CF3,
and/or if R1 denotes Cl, Br or CF3, then R4 denotes H.
Of these, the most preferred are compounds of formula I wherein
R1 denotes Me;
R2 denotes NR6R7, where
R6 denotes Me,
R7 denotes Me;
R3 denotes H, F, preferably H;
R4 denotes Cl or Br; and
R5 denotes H or Br,
and/or if R1 denotes Cl or Br, then R4 denotes H.
The compounds represented by formula I may be present in tautomeric equilibrium with the m-aminoanilino-2-imidazoline derivatives of formula II: 
in which the definitions of the groups R1, R2, R3, R4, R5, R6, and R7 are identical to the abovementioned compounds of formula I and all the preferences listed.
Therefore, the present invention also relates to the compounds which come under general formula II wherein the groups R1, R2, R3, R4, R5, R6, and R7 fall within the scope of the definitions given under formula I. The same is true of the preferred ranges mentioned under formula I.
The compounds which fall within the scope of definitions of formulae I and II are equally preferred, but independently of one another.
With regard to the nomenclature used within the scope of the present invention, it should be pointed out that the term xe2x80x9cphen-1xe2x80x2-yl-2-imidazolidinexe2x80x9d denotes compounds having the following structural element: 
This means that the atoms of the imidazole ring are numbered 1, 2, 3, etc., with one nitrogen atom being numbered 1 and the other nitrogen atom being numbered 3. Consequently, the imino group is bound to the carbon atom, which is assigned the number 2. The atoms of the phenyl ring are numbered 1xe2x80x2, 2xe2x80x2, 3xe2x80x2, etc., while the carbon atom of the phenyl ring which is bound to the imino group is designated 1xe2x80x2 throughout.
It is expressly mentioned that the corresponding tautomers according to general formula II are also included, even when they are not specifically mentioned. The same is true of all the m-aminoanilino-2-imidazolidine derivatives mentioned in the context of the present invention.
As representatives of all the compounds which come under general formula I or formula II, some m-dialkylaminophen-1xe2x80x2-yl-2-imidazolidines are mentioned hereinafter by way of example.
2xe2x80x2-Bromo-3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 1, preferably in the form of the hydrochloride, 
3xe2x80x2-bromo-5xe2x80x2-diethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 2, preferably in the form of the hydrochloride, 
3xe2x80x2-bromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 3, preferably in the form of the free base, 
3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 4, preferably in the form of the hydrochloride, 
2xe2x80x2-3xe2x80x2,-dibromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 5, preferably in the form of the free base 
2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 6, preferably in the form of the free base 
4xe2x80x2-bromo-2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 7, preferably in the form of the free base 
2xe2x80x2-bromo-6xe2x80x2-chloro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 8, 
5xe2x80x2-bromo-2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 9;
2xe2x80x2-bromo-5xe2x80x2-dimethylamino-6xe2x80x2-fluorophen-1xe2x80x2-yl-2-iminoimidazolidine 10;
3xe2x80x2-chloro-6xe2x80x2-fluoro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 11;
3xe2x80x2-chloro-4xe2x80x2-fluoro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 12;
6xe2x80x2-chloro-3xe2x80x2-fluoro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 13;
4xe2x80x2-chloro-3xe2x80x2-fluoro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 14;
3xe2x80x2-6xe2x80x2-dichloro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 15;
3xe2x80x2-4xe2x80x2-dichloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 16;
3xe2x80x2-4xe2x80x2-difluoro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 17;
3xe2x80x2-6xe2x80x2-difluoro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 18;
5xe2x80x2-dimethylamino-6xe2x80x2-methyl-2xe2x80x2-trifluoromethylphen-1xe2x80x2-yl-2-iminoimidazolidine 19; and
5xe2x80x2-dimethylamino-6xe2x80x2-methyl-3xe2x80x2-trifluoromethylphen-1xe2x80x2-yl-2-iminoimidazolidine 20.
Of these, the following are preferred:
2xe2x80x2-bromo-3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 1;
3xe2x80x2-bromo-5xe2x80x2-diethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 2;
3xe2x80x2-bromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 3;
3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 4;
2xe2x80x2-3xe2x80x2-dibromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 5;
2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 6;
4xe2x80x2-bromo-2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 7;
2xe2x80x2-bromo-6xe2x80x2-chloro-5xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 8; and
5xe2x80x2-bromo-2xe2x80x2-chloro-3xe2x80x2-dimethylaminophen-1xe2x80x2-yl-2-iminoimidazolidine 9;
and the pharmacologically acceptable salts thereof, particularly the hydrochlorides.
The following are particularly preferred:
2xe2x80x2-bromo-3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 1;
3xe2x80x2-bromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 3;
3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 4; and
2xe2x80x2-3xe2x80x2-dibromo-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 5;
and the pharmacologically acceptable salts thereof, particularly the hydrochlorides.
Most preferred is 3xe2x80x2-chloro-5xe2x80x2-dimethylamino-6xe2x80x2-methylphen-1xe2x80x2-yl-2-iminoimidazolidine 4and the pharmacologically acceptable salts thereof, particularly the hydrochloride.
Another aspect of the present invention relates to the compounds of the abovementioned general formulae I and/or II and the pharmacologically-compatible salts thereof with the groups R1 to R5 in all known definitions and pharmaceutical composition comprising the same.
Within the framework of the present invention, the definition of all named compounds is not only to include the free bases but also the respective pharmaceutically-acceptable acid addition salts. Acids suitable for this purpose may be both inorganic and organic by nature. Examples of suitable acids include: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, propionic acid, malic acid, succinic acid, amino acid, particularly glutamic acid or aspartic acid, carbohydrate acids and acids derived from carbohydrate. Salts of this kind may be important for galenic preparations both for increasing the stability, especially the long-term stability of the compounds and/or for increasing the bioavailability. Hydrochloride salts are preferred, either the monohydrochlorides or dihydrochlorides, depending on the particular compound. The same is true of the preferred compounds.
As already described hereinbefore, within the framework of the present invention the abovementioned compounds are distinguished over the compounds known from the prior art by their pharmacological properties, particularly with regard to their bioavailability and/or metabolism. It goes without saying that the most preferred compounds are those which have a high level of activity and bioavailability and a low metabolic breakdown. Another feature which is crucial when selecting particularly suitable compounds for treating urinary incontinence is the selectivity with which the compound in question acts on bladder function without seriously affecting other bodily functions, particularly the cardiovascular system.
Within the framework of the present invention, the named compounds and their pharmacologically-compatible acid addition salts can be prepared in suitable pharmaceutical formulations. This includes all formulations capable of being used medicinally. These are, for example, solutions, suspensions, aerosols, powders, tablets, coated tablets, suppositories, creams, etc.
The compounds according to the invention, the pharmacologically acceptable acid addition salts thereof and/or pharmaceutical preparations containing them may be used medicinally for treating diseases, especially diseases of the bladder, particularly in urinary incontinence. The compounds according to the invention are most preferably used for treating stress incontinence.
According to another aspect, the present invention relates to processes for preparing the abovementioned compounds, the pharmacologically acceptable acid addition salts and/or pharmaceutical preparations thereof, and the use of the compound described for preparing other pharmacologically active derivatives thereof.